Allogeneic transplantation for chronic myeloid leukemia: I'm not dead yet!
Authors: Jerald Radich
Journal: American Journal of Hematology (2022)

In 1957 E. Donnall Thomas presented data on six patients who received allogeneic bone marrow cells from unrelated donors.1 Most of these patients had received chemotherapy and/or radiation therapy for their underlying disease. Just think about how radical this was-HLA tissue typing was still many years in the future. Cell dose was estimated from very preliminary work in rodents and primates. How to best suppress the host immune system to prevent rejection was largely conjecture. Also of note: transplantation was being pursued not necessarily as a cure for hematological malignancies, but to potentially rescue radiation victims, as this catastrophe was widely seen as an inevitable consequence of the new nuclear age. As Dr. Thomas wrote in the Discussion of his NEJM article, "In an atomic age, with reactor accidents, not to mention stupidities with bombs, somebody is going to get more radiation than is good for him." CML was a special interest of Dr. Thomas' (and obviously, some of his mentees), and transplantation in CML became the modalities best early success story. Even early on, studies from Seattle showed (1) overall survival (OS) rates of ~50% in patients in first chronic phase, (2) a strong association of OS phase of disease, and (3) age dependent mortality, especially from transplant-related mortality (TRM).2 Times have changed, and the spectacular success of tyrosine kinase inhibitors has predictably and rightly consigned allogeneic transplant to the back burners of CML therapy. In this issue of the American Journal of Hematology, Chalandon et al.3 provide a retrospective analysis of nearly 1000 CML undergoing allogeneic transplant across many centers belonging to the European CML consortium. There are always limitations that come with such studies (selection bias of patients actually analyzed, not accounting for center-to-center differences in outcomes, etc.), but, a thousand patients is a thousand patients, so one suspects the data conclusions are reasonably robust. The findings are not altogether show stopping but are rather reassuring and are in accordance with other studies demonstrating the safety of TKIs pre-transplant.4 Regarding GVHD, patients treated with prior TKIs had historically stable incidences of acute and chronic GVHD, and there was no difference in the incidence or severity of GVHD associated with a particular TKI. The same was true with non-relapse mortality (NRM). Moreover, there was no difference in overall survival (OS) by type of TKI, nor (perhaps a tad surprising), the number of TKIs a patient had been exposed to. However, the analysis does not discriminate between patients who cycled through TKIs because of resistance, compared to intolerance, and did show that patients receiving ≥2 TKIs had a statistically significant increase in relapse rate. The firmest conclusion was that the strongest determinants of OS and relapse after transplant was being in anything but a first chronic phase, and a lower Karnofsky score. But the strongest message, the important message is, do not let patients get to advanced phase disease. And if you have an advanced phase case and manage to get them back into a second chronic phase, do not delay pursuing transplantation. CML in my lifetime has made a most remarkable treatment shift. In the 1980–1990 s, patients went to transplant ASAP. Today, we are on the opposite side of the spectrum, and physicians and patients often wait too long to transplant, hoping that the "N + 1"h TKI will magically eliminate resistance and/or intolerance where other TKIs have persistently failed. However, hope is not a plan. Thus, it is reasonable to at least begin preparing for the possibility of transplant (HLA typing of the patient, consultation with a transplant team, etc.) sooner than later when facing a patient with resistance, intolerance, or any signs of progression. If a new and improved TKI works in these settings, great, but if they do not, better to transplant in chronic phase than in advanced phase. When imatinib first hit the scene and the leukemia community was all abuzz, it then went by the compound name STI571. One of our colleagues liked to proclaim that STI stood for "stop transplants immediately." However, as this study suggests, transplant should not yet be declared dead. Instead, perhaps, STI should now mean, "some transplants indicated."